Triple negative breast cancers (TNBCs) are those devoid of estrogen and progesterone receptors and HER2 overexpression. They are heterogeneous cancers that disproportionately affect young women, African Americans and Hispanics. The prognosis for patients with metastatic TNBC is poor with only 30% surviving 5 years. There is an unmet need for more effective therapies for these breast cancers. Recent molecular profiling of TNBC tumors revealed 6 distinct subtypes with different molecular defects and identified cell lines representative of each of these subtypes. This information allows for the first time the opportunity for targeted drug discovery for each of the different subtypes of TNBC. The goal of this effort is to identify targeted therapies for the subtypes of TNBC. Many of the most successful drugs used to treat cancer are derived or modeled after compounds identified from nature. Natural products occupy a unique region of chemical space that overlaps extensively with pharmaceuticals and is not found in synthetic chemical libraries. Natural product extracts derived from diverse source organisms will be evaluated for the ability to selectively target cells representing the different subtypes of TNBC. An unprecedented collection of fungal extracts has been assembled from highly diverse environments ranging from deep lake sediments to road kill. The extensive biodiversity coupled with innovative culture conditions has yielded an exceptionally large collection of fungal extracts. A second source of chemical diversity will be obtained with extracts made from understudied Texas plants. Preliminary data from fungal and plant extracts show that lead extracts with greater than 100-fold selectivity against one TNBC subtype can be identified using high-content screening and secondary validation assays. Bioassay-guided fractionation of the active compounds will be conducted and those with selective activity will be identified. The pure compounds will be evaluated for in vitro efficacy and potency against multiple cell lines within a specific subtype o TNBC. The most promising compounds will be evaluated for chemical and metabolic stability, pharmacokinetic parameters and in vivo antitumor efficacy. Mechanism of action studies will be conducted to determine how these agents selectively target one subtype of TNBC and the pathways disrupted leading to selective cytotoxicity. These studies will discover new drug leads for consideration for clinical development and novel chemical probes that can identify signaling pathways of susceptibility for the distinct subtypes of TNBC. The ultimate goal of this effort is t identify effective molecularly targeted therapies with the potential to provide long-term disease control and overall survival for patients with TNBC.